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Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence

Oncogene volume 35, pages 5362–5376 (2016)Cite this article

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Abstract

Oncogenic Ras expression is associated with activation of the DNA damage response (DDR) pathway, as evidenced by elevated DNA damage, primarily DNA double-strand breaks (DSBs), and activation of DNA damage checkpoints, which in primary human cells leads to entry into senescence. DDR activation is viewed as a physiological barrier against uncontrolled proliferation in oncogenic Ras-expressing cells, and arises in response to genotoxic stress due to the production of reactive oxygen species that damage DNA and to hyper-replication stress. Although oncogene-induced senescence (OIS) is considered a tumor suppressor mechanism, the accumulation of DNA damage in senescent cells is thought to cause genomic instability, eventually allowing secondary hits in the genome that promote tumorigenesis. To date, the molecular mechanisms behind DNA repair defects during OIS remain poorly understood. Here, we show that oncogenic Ras expression in human primary cells results in the downregulation of BRCA1 and 53BP1, two key factors in DNA DSB repair by homologous recombination and non-homologous end joining, respectively. As a consequence, Ras-induced senescent cells are hindered in their ability to recruit BRCA1 and 53BP1 to DNA damage sites. Whereas BRCA1 is downregulated at transcripts levels, 53BP1 loss is caused by activation of cathepsin L-mediated degradation of 53BP1 protein. Moreover, we discovered a marked downregulation of vitamin D receptor (VDR) during OIS, and a role for the vitamin D/VDR axis regulating the levels of these DNA repair factors during OIS. This study reveals a new functional relationship between the oncogene Ras, the vitamin D/VDR axis and the expression of DNA repair factors, in the context of OIS. The observed deficiencies in DNA repair factors in senescent cells could contribute to the genomic instability that allows senescence bypass and tumorigenesis.

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Authors and Affiliations

  1. Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St Louis, MO, USA

    S Graziano, R Johnston & S Gonzalo

  2. Department of Radiation Oncology, School of Medicine Case Western Reserve University, Cleveland, OH, USA

    O Deng & J Zhang

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  1. S Graziano
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  2. R Johnston
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  3. O Deng
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  4. J Zhang
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  5. S Gonzalo
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Correspondence to S Gonzalo.

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Graziano, S., Johnston, R., Deng, O. et al. Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence. Oncogene 35, 5362–5376 (2016). https://doi.org/10.1038/onc.2016.77

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